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Shumaker SA, Legault C, Kuller L, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women: Women's Health Initiative Memory Study. JAMA. 2004;291(24):2947–2958. doi:https://doi.org/10.1001/jama.291.24.2947
Author Affiliations: Departments of Public Health Sciences (Drs Shumaker, Legault, and Coker) and Psychiatry and Behavioral Medicine (Dr Rapp), Wake Forest University School of Medicine, Winston-Salem, NC; Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pa (Dr Kuller); Department of Neurosciences, University of California at San Diego (Dr Thal); Department of Preventive Medicine, State University of New York at Stony Brook (Dr Lane); Institute for the Study of Aging, New York, NY (Dr Fillit); Stanford Prevention Research Center, Stanford University, Stanford, Calif (Dr Stefanick); Department of Obstetrics and Gynecology, Wayne State University School of Medicine/Hutzel Hospital, Detroit, Mich (Dr Hendrix); Department of Medicine, University of Alabama at Birmingham (Dr Lewis); Department of Geriatric Medicine, University of Hawaii, Honolulu (Dr Masaki).
Context The Women's Health Initiative Memory Study (WHIMS) previously found
increased risk for dementia and no effect on mild cognitive impairment (MCI)
in women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone
Objective To determine the effects of CEE alone and CEE plus MPA on incidence
of probable dementia and MCI in older women.
Design, Setting, and Participants Randomized, double-blind, placebo-controlled clinical trials of CEE
(estrogen-alone trial) or CEE plus MPA (estrogen plus progestin trial) in
community-dwelling women aged 65 to 79 years, conducted from June 1995 to
July 8, 2002 (estrogen plus progestin; n = 4532), or to February 29, 2004
(estrogen-alone; n = 2947), in 39 of the 40 WHI clinical centers.
Interventions In the estrogen-alone trial, 1 daily tablet containing either 0.625
mg/d of CEE vs matching placebo; in the estrogen plus progestin trial, 1 daily
tablet containing CEE (0.625 mg/d) plus MPA (2.5 mg/d) vs matching placebos.
Main Outcome Measures Probable dementia and MCI.
Results In the estrogen-alone trial, 47 participants were diagnosed with probable
dementia, of whom 28 were assigned to CEE and 19 to placebo (hazard ratio
[HR], 1.49; 95% confidence interval [CI], 0.83-2.66). Incidence rates for
probable dementia in the estrogen-alone trial were statistically similar to
those in the estrogen plus progestin trial (45 vs 22 per 10 000 person-years
for CEE plus MPA vs placebo, respectively; P = .11).
When data were pooled per the original WHIMS protocol, the overall HR for
probable dementia was 1.76 (95% CI, 1.19-2.60; P =
.005). After excluding participants with baseline Modified Mini-Mental State
Examination scores at or below the screening cut point, the HR was 1.77 (95%
CI, 0.74-4.23; P = .20) in the estrogen-alone trial
and 2.19 (95% CI, 1.25-3.84; P = .006) in the pooled
trials. In the estrogen-alone trial, 76 participants were diagnosed with MCI
in the CEE group vs 58 in the placebo group (HR, 1.34; 95% CI, 0.95-1.89).
In the combined trial data, the HR was similar (1.25; 95% CI, 0.97-1.60).
In the estrogen-alone trial, 93 participants receiving CEE were diagnosed
with either probable dementia or MCI vs 69 receiving placebo (HR, 1.38; 95%
CI, 1.01-1.89; P = .04).
Conclusions Estrogen therapy alone did not reduce dementia or MCI incidence and
increased the risk for both end points combined. Pooling data for estrogen
alone and estrogen plus progestin resulted in increased risks for both end
points. Use of hormone therapy to prevent dementia or cognitive decline in
women 65 years of age or older is not recommended.
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